The Role of High-Density Lipoprotein Oxylipins in Mild Cognitive Impairment and Neuroinflammation
Restricted (Penn State Only)
- Author:
- Kelliher, Julia
- Graduate Program:
- Integrative and Biomedical Physiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 01, 2023
- Committee Members:
- Gregory Shearer, Chair & Dissertation Advisor
Karolina Skibicka, Major Field Member
Donna Korzick, Program Head/Chair
Christopher Engeland, Outside Unit Member
Jennifer Graham-Engeland, Outside Field Member - Keywords:
- Oxylipin
oxylipins
HDL
high density lipoprotein
MCI
mild cognitive impairment
dementia
Alzheimer's
AD
Alzheimers
Lipids
PUFA
Oxidized lipids
Cognitive Impairment
Inflammation
Neuroinflammation
Systemic inflammation
Acute inflammatory challenge - Abstract:
- Dementia is a highly prevalent disorder that affected over 57 million people globally in 2019 and is projected to affect over 150 million people by 2050, particularly in low- and middle-income countries. The global economic burden of dementia in 2019 was 1.3 trillion United States dollars (USD) and this cost is predicted to increase to 2.8 trillion USD by 2030. Risk for dementia and dementia pathology is affected by excessive inflammation and dysregulated lipid homeostasis. Oxylipins are a diverse group of oxygenated lipid mediators produced from polyunsaturated fatty acids (PUFAs) that regulate inflammation and vascular homeostasis, among other processes. In the brain and periphery, oxylipins are transported by high-density lipoprotein (HDL), which maintains anti-inflammatory and vasoprotective properties. Higher systemic HDL concentrations reduce the risk for dementia, while impaired HDL lipid transport abilities are associated with increased dementia risk. Increasing evidence has linked altered oxylipin metabolism to neuroinflammatory diseases that include dementia, though the mechanisms of how oxylipins affect dementia pathology are still being elucidated. HDL trafficking of bioactive oxylipins may provide a critical mechanistic link between anti-inflammatory and vasoprotective HDL properties and HDL effects on cognitive impairment and dementia risk. In Study 1, we explored the effect of acute neuroinflammation on oxylipin profiles in Sprague Dawley rats and HT-22 mouse hippocampal neurons that were subjected to an interleukin-1beta (IL-1𝛽)-induced acute neuroinflammatory challenge. Oxylipins from rat cerebrospinal fluid (CSF), HDL plasma, and neuronal media and cells were extracted from biological samples using liquid-liquid extraction followed by solid-phase extraction. A panel of 60 oxylipins were quantified by targeted liquid chromatography with tandem mass spectrometry (LC/MS/MS). In rats, we examined the effects of neuroinflammation on HDL oxylipin concentration differences based on oxylipin location in plasma or CSF and based on rat sex. We found that acute neuroinflammation increased rat HDL oxylipin concentrations, particularly in CSF and in male rats. Interestingly, inflamed female rats had CSF oxylipin profile changes that were mirrored in plasma HDL. These results identify sex-specific activation of oxylipin signaling pathways during neuroinflammation, where male rats had mobilization of local CSF oxylipin signaling pathways, while female rats had promotion of both local and distant oxylipin trafficking in the CSF and plasma HDL. In hippocampal neurons, we studied the role of apolipoprotein (apo)A-I and apoE on oxylipin availability during neuroinflammation. We observed that apoA-I increased oxylipin availability in inflamed hippocampal neurons, providing support for apoA-I-dependent oxylipin trafficking during inflammation. In Study 2, we studied the effect of acute systemic inflammation on oxylipin profiles in Sprague Dawley rats and J774 mouse macrophages that were subjected to an IL-1𝛽- induced acute systemic inflammatory challenge. Oxylipins from rat CSF, HDL plasma, and macrophage media and cells were extracted from biological samples using liquid- liquid extraction followed by solid-phase extraction. A panel of 60 oxylipins were quantified by targeted LC/MS/MS. In rats, we examined the effects of systemic inflammation on HDL oxylipin concentration changes based on oxylipin location in plasma or CSF and based on rat sex. We found that acute systemic inflammation precipitated changes in central oxylipin profiles, where female rats had reduced amounts of omega (w)3 eicosapentaenoic acid (EPA) diols in both CSF and plasma HDL. As observed in Study 1, female but not male rats had central oxylipin profile changes that were mirrored in plasma HDL following the acute systemic inflammatory challenge. These results contribute molecular insight into sex differences in immunity. In macrophages, we studied the role of apoA-I on oxylipin availability during inflammation. Similarly to what was observed in hippocampal neurons, we found that apoA-I was associated with increased oxylipin availability in inflamed macrophages, further emphasizing the importance of apoA-I in oxylipin mobilization during inflammation. In Study 3, we examined HDL oxylipin profiles in older adults with or without mild cognitive impairment (MCI). HDL plasma was isolated from 223 racially diverse men and women with or without MCI who underwent extensive neurocognitive assessments and completed demographic psychosocial questionnaires. Oxylipins were extracted from HDL plasma using liquid-liquid extraction followed by solid-phase extraction, and a panel of 60 oxylipins were quantified by targeted LC/MS/MS. We explored how HDL oxylipin profiles differed by participant MCI status, gender, and race. We found that MCI status was associated with differing HDL oxylipin content and lower anti-inflammatory and vasodilatory w3 docosahexaenoic acid (DHA) and EPA oxylipin concentrations, particularly in men and Hispanic participants. These HDL oxylipin differences between non-MCI and MCI participants may reflect impaired anti-inflammatory and vasodilatory functions of HDL, especially in men and Hispanic individuals. To better understand oxylipin lipidome differences based on cognitive impairment severity, we utilized participant Montreal Cognitive Assessment (MoCA) scores with a score of 26 as a cutoff score between “normal MoCA” and “abnormal MoCA” to identify non-MCI participants with lower global cognitive function. We explored how HDL oxylipin profiles differed by participant cognitive status (non-MCI with normal MoCA, non-MCI with abnormal MoCA, and MCI with abnormal MoCA), gender, and race. Interestingly, in men and Hispanic participants, we observed a protective role for EPA diols against the presence of MCI in participants with abnormal MoCA scores. It is possible that loss of EPA diol concentrations contribute to worsened cognitive impairment and the development of MCI. We further assessed whether and how HDL oxylipin concentrations related to participant MoCA scores on a continuous scale using Spearman rank correlation and found that participant HDL oxylipin concentrations positively correlated with MoCA scores, especially for non-Hispanic white individuals. Overall, these gender- and race-specific HDL oxylipin profile differences in individuals with or without MCI identify specific dysregulated lipid signaling pathways in MCI and identify individuals who may experience the greatest cognitive benefit from interventions targeting lipid pathologies in dementia, such as w3 fatty acid supplementation. Taken together, the research described in this dissertation supports a role for HDL oxylipins in neuroinflammation and MCI. The observed sex-specific oxylipin concentration differences following the acute central and peripheral inflammatory challenges provide consistent evidence of activation of both local and distant oxylipin signaling pathways in females during inflammation and contribute molecular insight into sex differences in immunity. Further, apoA-I-dependent modulation of oxylipin availability in inflamed hippocampal neurons and macrophages suggests a biological mechanism for how HDL exerts its immunomodulatory effects. In individuals with or without MCI, lower concentrations of anti-inflammatory and vasodilatory oxylipins in HDL suggest impaired protective functions of HDL in individuals with MCI. Gender- and race-specific HDL oxylipin differences between non-MCI and MCI participants identify men and Hispanic individuals as people who may benefit most from interventions or prevention strategies that target lipid pathologies of dementia development, such as w3 fatty acid supplementation. Overall, these results identify specific altered lipid pathways in neuroinflammation and MCI and have implications for novel therapeutic targets and treatments for dementia.